Genetic competence is defined as a state in which bacterial cells are able to bind and internalize high molecular weight DNA, which may then be established as an independent replicon or recombine with a resident DNA molecule. Competence in Bacillus subtilis is one of several post-exponentially expressed systems, the most extensively studied of which is sporulation. The present study is directed towards unraveling the complex regulatory network that determines the onset of competence expression in response to environmental signals. This network is known to rely on quorum sensing, transmembrane signaling, phosphorylation events involving two-component regulators, protein-protein and protein-DNA interactions, transcriptional and posttranscriptional regulation as well as the action of ClpC, an HSP100-like protein. We will investigate the response of ComP to quorum-sensing ComX pheromones and we will determine the structure of the pheromone modification. We will study the interactions of MecA, ClpC and ComS which regulate the stability of the competence-specific transcription factor ComK. We will investigate the interactions of the five proteins known to bind at the comK promoter. We will study the factors responsible for the differentiation of two cell types in a competent culture, and the competence-specific growth arrest. Finally we will use expression profiling with genomic microarrays to study the global effects of mutations in competence regulatory genes. Quorum sensing and the ClpC heat shock protein regulate pathogenesis in a number of bacterial pathogens. Understanding the biology of the proteins involved may help to clarify the virulence mechanisms involved.